Method for processing a zirconium oxide composition in crystalline form

ABSTRACT

Methods of producing zirconium oxide compositions and using same are provided. The zirconium oxide compositions in crystalline form can be prepared by a synthetic process wherein the hydrolysis of zirconyl chloride and particle formation can be achieved simultaneously. Alternatively, the particle formation can occur first and then followed by hydrolysis with a base solution. The processes utilize a zirconyl salt solution that includes a zirconyl salt in isopropanol and water.

BACKGROUND OF THE INVENTION

[0001] The present invention relates generally to zirconium oxidecompositions. More specifically, the present invention relates tomethods of making and using zirconium oxide compositions in crystallineform that have an effective sorption capacity, such as for phosphates.

[0002] In general, materials are known and used to remove constituentsfrom fluids for a number of different applications including, forexample, industrial, recreational, therapeutic, diagnostic and/or thelike. For example, cationic polymers, anionic polymers and combinationsthereof are typically used to purify a variety of different aqueousstreams, such as industrial process streams, via ion exchange,flocculation or other suitable mechanism. Other materials are generallyknown as sorbent materials. The physiochemical properties of these typesof materials enable them to remove suitable types of constituents fromfluid via adsorption, absorbtion, chemisorption, chemical binding and/orother suitable mechanisms.

[0003] In general, materials are known in the art that are capable ofremoving phosphorous-containing constituents in solution. For example,zirconium oxide materials have been made by hydrolysis of a zirconiumsalt with a base. With these methods, the zirconium oxide is produced ina gel form. This can make it difficult to purify, such as by washingwith water using a redispersion and decantation method.

[0004] Zirconium oxides, in general, have been made in crystalline orgranular form. For example, particle formation is known to result fromadding a low dielectric medium to an aqueous solution of zirconium salt.In this regard, monodispersed, submicron and nanoscale (e.g.,<100 nm)zirconium oxide microspheres or powders have been synthesized underconditions that employ a 5:1 volume ratio of 2-propanol:water usinghydroxypropyl cellulose and ammonia neutralization.

[0005] This synthetic method can be problematic. For example, theparticle size of the zirconium oxide material is very fine in size, suchas less than 100 nanometers (nm) as previously discussed. Further, thezirconium oxide displays a substantially low phosphate sorptioncapacity.

[0006] A need, therefore, exists to provide zirconium oxide compositionsmade from improved methods with sorption properties that can beeffective even under physiological conditions and that can be readilyand easily made at reduced costs, and easily adapted to existingsystems, such as therapeutic systems.

SUMMARY OF THE INVENTION

[0007] The present invention relates to zirconium oxide compositions. Inparticular, the present invention relates to improved methods of makingand using zirconium oxide compositions in crystalline or granular formthat display effective sorption capacity, particularly with respect tophosphorous-containing constituents, such as phosphate ions.

[0008] In an embodiment, the zirconium oxide compositions are producedby preparing a reaction solution that includes a base solution and azirconyl salt solution wherein the zirconyl salt solution includes azirconyl salt in isopropanol and water. The reaction solution is mixedand heated at a reflux temperature, thereby forming a zirconium oxideprecipitate. The precipitate can then be washed, dried and furtherprocessed prior to use.

[0009] In another embodiment, the zirconium oxide compositions areproduced by preparing a zirconyl salt solution that includes a zirconylsalt in isopropanol and water. The zirconyl salt solution is heated at areflux temperature. A base solution is added to the zirconyl saltsolution at the reflux temperature, thereby forming a zirconium oxideprecipitate. The precipitate can then be washed, dried and furtherprocessed prior to use.

[0010] As previously discussed, zirconium oxide compositions madepursuant to an embodiment of the present invention can display aneffective sorption capacity, particularly with respect tophosphorous-containing constituents. This can be particularly beneficialas applied during regenerative dialysis therapy where the dialysate isregenerated prior to reuse, such as recirculation into, through and outof a patient's peritoneal cavity during continuous flow peritonealdialysis. In this regard, the zirconium oxide compositions of thepresent invention can be adapted in any suitable way to remove at leasta portion of phosphate ions, other suitable metabolic waste, suitableother biological matter and the like from the dialysate prior to reuse.It should be appreciated that the zirconium oxide compositions of thepresent invention can be utilized in a variety of different and suitableapplications with respect to and in addition to dialysis therapy.

[0011] Further, the zirconium oxide compositions made pursuant to anembodiment of the present invention have a large particle size. Thisallows the composition to be readily purified, such as by washing withwater and/or other suitable purification techniques.

[0012] In yet another embodiment, the present invention provides amethod of increasing sorption capacity of a zirconium oxide compositionin crystalline form made pursuant to an embodiment of the presentinvention.

[0013] An advantage of the present invention is to provide improvedmethods for making zirconium oxide compositions.

[0014] Another advantage of the present invention is to provide improvedmaterials, devices, apparatuses and systems that utilize zirconium oxidecompositions made according to an embodiment of the present invention.

[0015] Yet another advantage of the present invention is to provideimproved zirconium oxide compositions in crystalline form that displayan enhanced sorption capacity for phosphorous-containing constituentsand/or the like.

[0016] Yet still another advantage of the present invention is toprovide improved zirconium oxide compositions in crystalline form thatcan bind phosphorous-containing constituents and/or the like underphysiological conditions.

[0017] A still further advantage of the present invention is to providezirconium oxide compositions that can be made pursuant to an embodimentof the present invention with relative ease, at reduced costs and highyields.

[0018] A further advantage of the present invention is to provideimproved zirconium oxide compositions that can remove phosphates and/orthe like from solutions used during medical therapy, such as dialysis.

[0019] Additional features and advantages of the present invention aredescribed in, and will be apparent from, the following DetailedDescription of the Invention and the figures.

BRIEF DESCRIPTION OF THE FIGURES

[0020]FIG. 1 is a schematic illustration of a system including a devicecontaining a zirconium oxide composition according to an embodiment ofthe present invention.

[0021]FIG. 2 is a schematic illustration of a chemical cartridge that atleast includes a zirconium oxide composition made pursuant to anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention generally relates to zirconium oxidecompositions. More specifically, the present invention relates tomethods of making and using zirconium oxide compositions that display aneffective sorption capacity for phosphorous-containing constituents.

[0023] In general, the processes of the present invention provide acrystalline or granular form of zirconium oxide that are relatively easyand inexpensive to make. In crystalline form, the zirconium oxide can bereadily purified. In this regard, the zirconium oxide crystals orgranulated particles have a large particle size. In an embodiment, theparticle size is greater than about 10 microns.

[0024] As previously discussed, the zirconium oxide compositions displayenhanced sorption capacity, particularly with respect tophosphate-containing constituents, such as anions, molecules or radicalscontaining heteroatoms with free electron pairs including phosphorous,such as phosphates. In an embodiment, the zirconium oxide compositionsdisplay a sorption capacity of greater than about 20 milligrams (mg) ofphosphorous/gram (g) of zirconium oxide. Preferably, the zirconium oxidecompositions have a sorption capacity that ranges from about 27 mg to atleast about 29 mg of phosphorous per gram of zirconium oxidecomposition. This makes the zirconium oxide compositions made pursuantto an embodiment of the present invention useful for a variety ofdifferent applications, particularly with respect to therapeutictherapies, such as dialysis therapy as described below.

[0025] With respect to dialysis therapy, the present invention can beused in a variety of different dialysis therapies to treat kidneyfailure. Dialysis therapy as the term or like terms are used throughoutthe text is meant to include and encompass any and all forms oftherapies to remove waste, toxins and excess water from the patient. Thehemo therapies, such as hemodialysis, hemofiltration andhemodiafiltration, include both intermittent therapies and continuoustherapies used for continuous renal replacement therapy (CRRT). Thecontinuous therapies include, for example, slow continuousultrafiltration (SCUF), continuous venovenous hemofiltration (CVVH),continuous venovenous hemodialysis (CVVHD), continuous venovenoushemodiafiltration (CVVHDF), continuous arteriovenous hemofiltration(CAVH), continuous arteriovenous hemodialysis (CAVHD), continuousarteriovenous hemodiafiltration (CAVHDF), continuous ultrafiltrationperiodic intermittent hemodialysis or the like. The present inventioncan also be used during peritoneal dialysis including, for example,continuous ambulatory peritoneal dialysis, automated peritonealdialysis, continuous flow peritoneal dialysis and the like. However, itshould be appreciated that the compositions of the present invention canbe effectively utilized with a variety of different applications,physiologic and non-physiologic, in addition to dialysis.

[0026] As previously discussed, the present invention generally providesmethods of making zirconium oxide compositions in crystalline orgranular form with a sorption capacity effective for use in a number ofdifferent applications, particularly as applied to dialysis therapy. Forexample, the zirconium oxide compositions can be prepared by a syntheticprocess wherein the hydrolysis of zirconyl chloride and particleformation can be achieved simultaneously as described below.Alternatively, the particle formation can be achieved first and thenfollowed by hydrolysis with a base solution.

[0027] In an embodiment, a method of producing a zirconium oxidematerial includes preparing a reaction solution that includes a basesolution and a zirconyl salt solution wherein the zirconyl salt solutionincludes a zirconyl salt in isopropanol and water. The reaction solutionis mixed and then heated at a reflux temperature, thereby forming azirconium oxide precipitate. The precipitate can be washed, dried andfurther processed for use.

[0028] In another embodiment, the zirconium oxide compositions can beprepared as follows. In an initial step, a zirconyl salt solution isprepared that includes a zirconyl salt in isopropanol and water. Thesolution is then heated to a reflux temperature and a base solution isadded to the solution at the reflux temperature, thereby forming thezirconium oxide precipitate. The precipitate can then be washed, driedand further processed prior to use.

[0029] It should be appreciated that the synthetic processes of thepresent invention can be carried out in any suitable manner. Forexample, the reaction solution can be prepared with any suitable typeand amount of zirconyl salt, base solution and other suitable reactioncomponents. In an embodiment, the zirconyl salt includes a zirconylchloride octahydrate or other suitable zirconium-containing compound;and the base solution includes a base material, such sodium hydroxide,ammonium hydroxide, combinations thereof and the like. The base solutioncan include any suitable concentration, preferably about 10 Normal (N).The zirconyl salt solution can be made from any suitable amount ofisopropanol and water. In an embodiment, the volume ratio of isopropanolto water in the zirconyl salt solution ranges from about 5:1 to about2:1.

[0030] The reaction solution can be processed at any suitabletemperature over any sufficient period of time. In an embodiment, thereaction solution that includes a base solution and a zirconyl saltsolution is first mixed at room temperature for about 2 hours to about20 hours, thereby forming a white precipitate. Preferably, the basesolution is added slowly to a stirred zirconyl salt solution. Next, thereaction solution is heated to a reflux temperature and maintained atthe reflux temperature for about 2 hours to about 20 hours, after whichtime a heavy white zirconium oxide precipitate is formed.

[0031] The white precipitate is isolated by decantation and washed in asolvent, such as water, ethanol, combinations thereof or the like. Forexample, the precipitate can be isolated by decantation, washed solelywith water or with water followed by ethanol using redispersion inwater, ethanol or the like, and decantation methods. After washing, theprecipitate is dried at a suitable temperature, such as about 80° C. toabout 110° C. In an embodiment, the precipitate is dried over anextended period, such as overnight.

[0032] In another embodiment, the zirconyl salt solution is heated toreflux for about 1 hour to about 6 hours to induce particle formation.The base solution is then added to the zirconyl salt solution, and themixture is heated to reflux and maintained for about 1.5 hours to about20 hours to complete hydrolysis, thus yielding a heavy whiteprecipitate.

[0033] The precipitate is isolated by decantation and washed in asolvent, such as water, ethanol, combinations thereof or the like, andoptionally adjusted to a desired pH and is again washed. In anembodiment, the precipitate is finally washed with water alone or washedwith water followed with ethanol using redispersion and decantationmethods. After washing, the precipitate is dried at a suitabletemperature overnight, such as about 60° C. to about 110° C. In anembodiment, the precipitate is dried for a lengthened period, such asovernight.

[0034] By way of example and not limitation, the following examples areillustrative of how to make the zirconium oxide compositions accordingto an embodiment of the present invention and further illustrateexperimental tests conducted on zirconium oxide compositions made inaccordance with an embodiment of the present invention.

[0035] Synthesis of Zirconium Oxide (ZO)

[0036] The zirconium oxide compositions were, in general, made accordingto two types of synthetic procedures (Methods I and II). Under theMethod I procedure, the hydrolysis of zirconyl chloride and particleformation essentially occurred at the same time according to anembodiment of the present invention as previously discussed. Under theMethod II procedure, the particle formation occurred first and wasfollowed by hydrolysis according to another embodiment of the presentinvention as previously discussed.

[0037] Method I—ZO Composition One

[0038] Step 1: Isopropanol (156.4 mL) was added to a stirred solution ofzirconyl chloride octahydrate (64.45 g, 200 mmol) in water (35 mL) togive a turbid solution. To this solution, while stirring, 10 N NaOH(43.2 mL, 432 mmol) was added dropwise over 15 minutes and then stirredat room temperature for 2 hours. Stirring was stopped, and theprecipitate was allowed to settle.

[0039] Step 2: The supernatant (170 mL) was discarded by decantation,and isopropyl alcohol (150 mL) was added. The mixture was stirred andheated to reflux for 20 hours.

[0040] Step 3: After refluxing, the reaction mixture was cooled to roomtemperature and the supernatant was removed by decantation. Theprecipitate was washed by repeated cycles of redispersion in water (500mL) and decantation. Washing was continued until the conductivity of thesupernatant reached 460 μS/cm (9 cycles). The precipitate was isolatedby filtration. The wet precipitate was divided into two equal portions.A first portion was dried at 110° C. overnight to give a product (11.13g). A second portion was washed with ethanol (300 mL) by redispersionand decantation method. Washing was continued for two cycles, and theproduct was isolated by filtration and dried at 80° C. overnight to giveanother product (10.27 g).

[0041] Method I—ZO Composition Two

[0042] Step 1: Isopropyl alcohol (312.8 mL) was added to a stirredsolution of zirconyl chloride octahydrate (128.9 g, 400 mmol) in water(70 mL) to give a turbid solution. Sodium hydroxide (10 N, 86.4 mL, 864mmol) was added dropwise over 15 minutes to give a white precipitate.The mixture was stirred at room temperature for 2 hours.

[0043] Step 2: The stirred reaction mixture was heated to reflux for 20hours and then cooled to room temperature, and the precipitate wasallowed to settle.

[0044] Step 3: The supernatant was discarded, and the precipitate waswashed by repeated cycles of redispersion in water (500 mL) anddecantation. Washing was continued until the conductivity of thesupernatant reached 650 μS/cm (7 cycles). The precipitate was thenstirred with water (500 mL), and the pH of the mixture was adjusted to7.0 using 1N HCl (24 mL). After pH adjustment, the mixture was allowedto settle down, and the clear supernatant was discarded by decantation.The precipitate was washed by repeated cycles of redispersion in water(1L) and decantation. Washing was continued until the conductivity ofthe supernatant reached 11.6 μS/cm (3 cycles). The wet precipitate wasdivided into two equal portions. A first portion was dried at 80° C.overnight to give one product (16.74 g). A second portion was dried at110° C. overnight to give another product (15.18 g).

[0045] Method II—ZO Composition Three

[0046] Step 1: Isopropyl alcohol (280 mL) was added to a stirredsolution of zirconyl chloride octahydrate (128.9 g, 400 mmol) in water(70 mL) to give a turbid solution. The solution was heated to reflux for2 hours to produce a white precipitate.

[0047] Step 2: Heating was stopped and 10N NaOH (86.4 mL, 864 mmol) wasadded dropwise while stirring over 10 minutes. After NaOH addition,heating to reflux was resumed.

[0048] Step 3: After refluxing for 20 hours, the reaction mixture wascooled to room temperature and the supernatant was discarded bydecantation. The precipitate was washed by repeated cycles ofredispersion in water (1L) and decantation. A small amount of finematerials formed in the reaction mixture was eliminated by thedecantation method. Washing was continued until the conductivity and thepH of the supernatant reached 593 μS/cm and 10.5, respectively. The wetprecipitate, which was isolated by vacuum filtration, was divided intofour equal portions. A first portion was dried at 110° C. overnight togive one product (11.49 g). A second portion was dried at 80° C.overnight to give another product (11.86 g).

[0049] Third and fourth portions were combined, stirred with water (450mL), and the pH of the mixture was adjusted to 7.0 with 1N HCl (13 mL).After pH adjustment, the precipitate was washed by repeated cycles ofredispersion in water (500 mL) and decantation. The supernatant of thelast wash cycle (3) had a pH of 7.0 and conductivity of 12.8 μS/cm. Thewet precipitate was divided into two equal portions. A portion was driedat 110° C. overnight to give one product (10.6 g). Another portion waswashed with ethanol (300 mL) by redispersion and decantation methods (2cycles). The precipitate was dried at 80° C. overnight to give anotherproduct (11.09 g).

[0050] Method II—ZO Composition Four

[0051] Step 1: Isopropyl alcohol (210 mL) was added to a stirredsolution of zirconyl chloride octahydrate (128.9 g, 400 mmol) in water(70 mL) to give a turbid solution. The solution was heated to reflux for2 hours to give a white precipitate.

[0052] Step 2: Heating was stopped and 10 N NaOH (86.4 mL, 864 mmol) wasadded to the stirred reaction mixture over 20 minutes. Heating to refluxwas resumed.

[0053] Step 3: After refluxing for 20 hours, the reaction mixture wascooled to room temperature, and the solid was allowed to settle. Thesupernatant was discarded, and the precipitate was washed by repeatedcycles of redispersion in water (500 mL) and decantation, until theconductivity and pH of the supernatant reached 1.7 μS/cm and 11.5,respectively (7 cycles). After washing, the pH of the precipitate inwater (500 mL) was adjusted to 7.0 with 1N HCl (42 mL). The supernatantwas discarded by decantation and the precipitate was washed by repeatedcycles of redispersion and decantation (3 cycles). The wet precipitatewas divided into four equal portions. Portion one was dried under housevacuum filtration overnight to give one product (14.11 g). Portion twowas dried at 60° C. overnight to give a second product (11.95 g).Portion three was dried at 80° C. overnight to give a third product(12.16 g). Portion four was dried at 110° C. overnight to give a fourthproduct (10.95 g).

[0054] Method II—ZO Composition Five

[0055] Step 1: Isopropyl alcohol (5.25 L) was added to a stirredsolution of zirconyl chloride octahydrate (3.2 kg, 10 mol) in water(1.75 L) to give a turbid solution. The solution was heated to refluxfor 2 hours to give a white precipitate.

[0056] Step 2: Heating was stopped, and 10 N NaOH (2.16 L, 21.6 mol) wasadded to the stirred reaction mixture over 20 minutes. Heating to refluxwas resumed.

[0057] Step 3: After refluxing for 20 hours, the reaction mixture wascooled to room temperature and the solid allowed to settle. Thesupernatant was discarded, and the precipitate was washed by repeatedcycles of redispersion in water (15L) and decantation until theconductivity and pH of the supernatant reached 2.3 μS/cm and 11.5,respectively (9 cycles). After washing, the pH of the precipitate inwater (15 L) was adjusted to 7.2 with 5N HCl (187 mL). The supernatantwas discarded by decantation, and the precipitate was washed by repeatedcycles of redispersion (6 L) and decantation (5 cycles). The precipitatewas collected via vacuum filtration over a Whatman #54 paper andvacuumed until no more fluid passed through the Buchner funnel. Thefilter cake was then transferred to a drying pan and dried at 110° C.overnight (approximately 15 hours) to give a product (902 g).

[0058] Phosphorous Sorption Capacity Experiments

[0059] Zirconium oxide compositions made according to an embodiment ofthe present invention as previously discussed were subjected to adynamic test system for determination of phosphorous sorption capacity.The experimental procedures and results are detailed below.

[0060] In general, a column was packed with a zirconium oxidecomposition test sample and a mobile phase was passed through thecolumn. Mobile phase fractions were collected at various time periodsand analyzed for pH, phosphorous and other analytes.

[0061] In particular, a BIORAD BIO-SCALE column (MT2, Cat. No. 751-0081)was packed with the zirconium oxide test sample according to knownprocedures. The mobile phase included a BAXTER DIANEAL PD-1 solutionthat was spiked with sodium phosphate (NaH₂PO₄: SIGMA, Cat. No. S-8282)to a level of 3 mg/dL of phosphorous. The mobile phase was pumped (pump:APPLIED BIOSYSTEMS, MODEL 400 SOLVENT DELIVERY SYSTEM) through thecolumn at 2 mL/min over a period of 460 minutes.

[0062] Fractions (4 mL) were collected at various time intervals(minutes) as follows: 0, 2, 4, 6, 8, 10, 20, 30, 40, 50, 60, 70, 80, 90,100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230,240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370,380, 390, 400, 410, 420, 430, 440, 450, and 460. The collected fractionswere then analyzed for calcium (Ca), phosphorous (P), magnesium (Mg),sodium (Na), and pH using the following clinical chemistry analyzers: 1)Ca: ROCHE, BOEHRINGER MANNHEIM, Cat. No. 1489216, COLORIMETRIC METHOD,INSTRUMENT HITACHI 911; 2) P: ROCHE, BOEHRINGER MANNHEIM, Cat. No.1040898, AMMONIUM PHOSPHOMOLYBDATE METHOD, INSTRUMENT HITACHI 911; 3)Mg: ROCHE, BOEHRINGER MANNHEIM, Cat. No. 1489330, COLORIMETRIC METHOD,INSTRUMENT HITACHI 911; 4) Na: ROCHE, BOEHRINGER MANNHEIM, Cat. No.371037, ISE TECHNOLOGY, INSTRUMENT HITACHI 911; and 5) pH: ORION pHmeter.

[0063] The phosphorous capacity was calculated as follows:$\frac{\lbrack P\rbrack \left( {\text{mg/dL)}_{Feed} \cdot \text{Flow Rate(mL/min)} \cdot {B.T.\left( \min \right)} \cdot 0.01} \right.}{{ZO}\quad (g)} = \text{Capacity (mg/g)}$

[0064] where [P] (mg/dL)_(Feed) is the phosphorous concentration in themobile phase, Flow Rate (mL/min) is the rate at which the mobile phaseis pumped, B.T. (min) is the last time point (fraction) at which thephosphorous concentration is less than or equal to 10% of thephosphorous feed concentration (i.e., 0.6 mg/dL), and ZO is the weightof zirconium oxide packed in the column.

[0065] The capacity results are indicated below in Tables I and II.Table I represents phosphorous capacity tests conducted on zirconiumoxide compositions made pursuant to Method I according to an embodimentof the present invention as previously discussed. Table II representsphosphorous capacity tests conducted on zirconium oxide compositionsmade pursuant to Method II according to an embodiment of the presentinvention as previously discussed. TABLE I METHOD I^(a) Step 1 10 N Step2 Step 3 Phosphorous ZO ZrOCl₂g Water IPA NaOH IPA/ Temp.° C./ Temp.°C./ Washing, pH Yield Cap. Density Product (mmol) (mL) (mL) (mL) WaterTime, hr.^(b) Time, hr.^(c) adj., and drying^(d) (g)^(i) (mg P/g ZO)(g/mL) ZO-A1  32.225 20 315 43.2 5/1 RT/2 Reflux/2 E-B80 11.6 >29.10.677 (100) (5 N) ZO-A2  32.225 18 183 21.6 4.6/1   RT/1.25 Reflux/3E-B80 12.2 — 0.697 (100) ZO-A3  32.225 18 183 21.6 4.6/1   RT/20 — E-B8010.1^(e) 7.5 0.823 (100) ZO-A4  32.225 18 158 21.6 4/1 RT/2 Reflux/3E-B80 11.8^(e) 23.9 0.830 (100) ZO-A5  64.45 36 238 43.2 3/1 RT/2Reflux/3 E-B80 16.5^(f) >29.1 0.574 (200) ZO-A6  64.45 36 158 43.2 2/1RT/2 Reflux/3^(g) E-B80 17.2^(f) >28.4 0.515 (200) ZO-A7  64.45 45 88.243.2 1/1 RT/2 Reflux/3^(g) E-B80 8.2^(f) >28.7 0.422 (200) W-B110 11.027.0 0.719 ZO-A8  64.45 45 88.2 43.2 1/1 RT/2 Reflux/3^(h) E-B6011.8 >28.3 0.533 (200) W-B110 9.8 24.4 0.937 ZO-A9  64.45 35 156 43.22/1 RT/2 Reflux 3^(h) E-B60 9.7 39.3 0.718 (200) W-B110 8.9 16.5 1.039ZO-A10  64.45 35 156 43.2 2/1 RT/2 Reflux/20^(h) E-B60 11.1 39.3 0.570(200) W-B110 10.3 26.8 0.836 ZO-A11 128.9 70 313 86.4 2/1 RT/2 Reflux/20W-N80 16.7 23.3 0.807 (400) W-N110 16.2 26.8 — # (110); W-N110: Productwas washed with water (W), pH was adjusted to 7 (N), dried at 110° C.(110); and E-B60: Product was washed with water followed by ethanol (E),no pH adjustment (B), dried at 60° C. (60).

[0066] TABLE II METHOD II^(a) Step 1 Step 2 Step 3 IPA/ Temp./ 10 NTemp. Washing, pH Phosphorous ZO ZrOCl₂ g Water IPA Water Time, NaOH °C./Time, adjustment, Yield Cap. Density Product (mmol) (mL) (mL) (v/v)hr. (mL) hr.^(b) and Drying^(h) (g)^(g) (mg P/g ZO) (g/mL) ZO-B1^(c) 32.335 33 165 5/1 Reflux/1 43.2 Reflux/1.5 E-B80 13.2^(d) >29.3 0.677(100) (5 N) ZO-B2  64.45 35 175 5/1 Reflux/1.25 43.2 Reflux/3 E-B8011.0^(e) >28.7 0.558 (200) W-B110 10.6 23.6 1.180 ZO-B3  64.45 35 1755/1 Reflux/2 43.2 Reflux/3 E-B80 11.0^(e) >28.5 0.771 (200) W-B110 10.719 1.162 ZO-B4^(c)  64.45 45 175 3.89/1   Reflux/1.25 43.2 Reflux/3E-B80 11.3^(e) 40.4 0.647 (200) W-B110 11.3^(e) 18.8 1.114 ZO-B5  64.4535 140 4/1 Reflux/2 43.2 Reflux/3 E 12.0 >29.4 0.798 (200) W 11.2 19.71.169 ZO-B6  64.45 35 105 3/1 Reflux/2 43.2 Reflux/3 E 8.6 41.7 0.554(200) W 7.8 24.8 0.959 ZO-B7  64.45 35 140 4/1 Reflux/4 43.2 Reflux/3E-B60 10.7 >27.6 1.011 (200) W-B110 9.1 17.3 1.153 ZO-B8  64.45 35 1404/1 Reflux/2 43.2 Reflux/20 E-B60 11.5 >28.1 0.934 (200) W-B110 9.8 23.31.122 ZO-B9  64.45 35 140 4/1 Reflux/2.2 43.2 Reflux/3 E-B60 10.7 >30.10.720 (200) W-B110 10.1 23.4 1.096 ZO-B10  64.45 35 140 4/1 Reflux/643.2 Reflux/17 E-B60 8.6 31.9 0.577 (200) W-B110 8.3 26.0 1.068 ZO-B11128.9 70 280 4/1 Reflux/2 86.4 Reflux/20 W-B110 11.5 26.9 1.045 (400)W-B80 11.9 22.3 1.054 W-N110 10.6 26.2 1.054 E-N80 11.1 38.7 0.553ZO-B12 128.9 70 280 4/1 Reflux/2 86.4 Reflux/20 W-N25 13.7 26.8 1.147(400) W-N60 11.6 28.1 1.037 W-N80 12.1 28.7 1.006 W-N110 11.0 28.7 0.965ZO-B13 128.9 70 210 3/1 Reflux/2 86.4 Reflux/20 W-N25 14.1 27.5 1.167(400) W-N60 12.0 28.5 1.017 W-N80 12.2 28.5 0.965 W-N110 11.0 29.0 0.983ZO-B14 128.9 70 140 2/1 Reflux/2 86.4 Reflux/20 W-N25 11.8 27.6 0.834(400) W-N60 10.4 27.6 0.786 W-N80 10.2 29.4 0.744 W-N110 9.9 27.6 0.766ZO-B15 3.2 kg 1.75 L 5.25 L 3/1 Reflux/2 2.16 L Reflux/20 W-N110 90227.5 0.952 (10 mol) # (110); W-B: Product was washed with water (W), nopH adjustment (B) and dried at 80° C. (80) or 110° C. (110); and W-N:Product was washed with water (W), pH was adjusted to 7.0(N), and driedto 25° C. (25), 60° C. (60), 80° C. (80) or 110° C. (110).

[0067] In general, the zirconium oxide compositions produced by MethodII had a higher density than the zirconium oxide compositions producedby Method I. The density of the ethanol washed zirconium oxide (0.5-0.9g/mL) was lower than the density of the water washed zirconium oxide(1.6-1.1 g/mL). This indicates that ethanol washed zirconium oxide ismore porous than the water washed zirconium oxide, and as a consequence,it has a higher phosphorous sorption capacity (e.g., about 30 to about40 mg/g for ethanol washed zirconium oxide as compared to about 20 toabout 30 mg/g for water washed zirconium oxide).

[0068] In general, the density of zirconium oxide decreases with adecreasing isopropanol/water ratio, particularly with respect to thezirconium oxide compositions made according to Method I procedures. Withrespect to Method II procedures, a decrease in density was observed whenthe isopropanol/water ratio of 2/1 was used. The capacity tests alsoindicated that longer refluxing times (e.g., about 20 hours) for thehydrolysis are preferred. In this regard, a higher phosphorous sorptioncapacity was consistently obtained as shown in Tables I and II.

[0069] Methods I and II produced zirconium oxide compositions that werewhite in color and that had a large particle size in powder form. Thisallowed the compositions to be easily washed with water/ethanol byredispersion and decantation methods, thus facilitating the large-scalesynthesis of zirconium oxide. Further, acceptable column backpressurelevels were observed during the dynamic capacity test.

[0070] The test results also demonstrated that an effective sorptioncapacity can be achieved with a large-scale synthesis of zirconium oxidecompositions made pursuant to an embodiment of the present invention.The reaction parameters for large-scale synthesis were based on thefollowing factors: a) designing a relatively simple process forzirconium oxide synthesis; b) obtaining a large particle size atdesirable levels of product yields; c) obtaining a desirable level ofphosphorous sorption capacity, such as within or exceeding a phosphoroussorption capacity that ranges from about 27 to about 29 mg ofphosphorous/g of zirconium oxide; and d) obtaining a desirable level ofproduct density, such as within or exceeding a density that ranges fromabout 0.9 g/mL to about 1.1 g/mL.

[0071] The zirconium oxide compositions made pursuant to an embodimentof the present invention can effectively remove via sorption anysuitable number, type and amount of constituents from a fluid,particularly phosphorous-containing constituents including anions,molecules, radicals and the like. It should be appreciated that thezirconium oxide compositions of the present invention can removeconstituents from any suitable fluid existing in liquid phase, gaseousphase, mixed liquid and gaseous phase, supercritical systems and/or thelike.

[0072] The sorption properties make the zirconium oxide compositions ofthe present invention well suited for a variety of differentapplications subject to physiological and/or non-physiologicalconditions. In an embodiment, the zirconium oxide compositions of thepresent invention can be used to remove phosphorous-containingconstituents or the like from blood and/or solutions used to dialyzeblood. In this regard, the present invention provides materials,devices, apparatuses and systems that can utilize zirconium oxidescompositions made pursuant to an embodiment of the present invention toremove constituents from fluids, such as phosphorous-containingconstituents from blood and/or solutions used to dialyze blood aspreviously discussed.

[0073] In an embodiment, the present invention includes devices thatutilize the zirconium oxide compositions made pursuant to an embodimentof the present invention to remove phosphorous-containing constituentsor the like from fluids. In general, the device 10 includes a body 12defining an interior 14 through which a fluid can pass into the device10 via an inlet 16 and optionally flow out of the device via an outlet18 as shown in FIG. 1. The device 10 contains the zirconium oxidecomposition or material thereof 20 made according to an embodiment ofthe present invention in its interior 14. The device 10 can contain thezirconium oxide material in any suitable way, such as in a layeredconfiguration. As the fluid passes through the device, the zirconiumoxide composition can act to remove phosphorous-containing constituentsor the like from the fluid.

[0074] As previously discussed, the present invention provides a systemcapable of removing a constituent from a fluid. The system can beapplied in a variety of different applications including, for example,therapeutic and diagnostic applications. In an embodiment, the system 22includes a fluid pathway through which the fluid can flow that iscoupled to the device 10 as discussed above and as shown in FIG. 1. Thefluid pathway at least includes an inflow fluid path 24 allowing fluidto enter the device. Optionally, a number of other suitable fluidpathways can be coupled to the device, such as an outflow fluid path 26allowing the fluid to pass through and out of the device 10.

[0075] As applied, the device is particularly suited for removal ofphosphorous-containing constituents from a dialysis solution duringdialysis therapy. In an embodiment, the device includes a chemicalcartridge coupled in any suitable manner to a patient loop (not shown)through which dialysate is circulated into, through and out of thepatient during dialysis therapy, such as continuous flow peritonealdialysis. In this regard, the device can be used to remove atherapeutically effective amount of a phosphorous-containing constituentfrom the dialysis solution as it continually or intermittently passesthrough the device prior to circulation into, through and out of thepatient. This can enhance dialysis clearance and minimize the amount ofdialysis fluid necessary to maintain effective clearance levels duringdialysis therapy.

[0076] It should be appreciated that the chemical cartridge can includeany suitable number, type and amount of materials in addition to thezirconium oxide compositions made pursuant to an embodiment of thepresent invention in order to enhance treatment. An example of achemical cartridge according to an embodiment of the present inventionis disclosed in U.S. patent application Ser. No. 09/990,673, filed onNov. 13, 2001, and entitled “Method and Compositions for Removing UremicToxins in Dialysis Processes,” the disclosure of which is incorporatedherein by reference.

[0077] Referring now to FIG. 2, a cross-sectional view of an embodimentof the cartridge 32 of the present invention is illustrated. Thecartridge 32 includes a resin bed 34 that is designed to modify thechemistry of the recirculating dialysate and remove uremic toxins. Atthe same time, pursuant to the present invention, the cartridge 32maintains electrolyte concentrations and the solution pH of thedialysate at physiologic levels.

[0078] The cartridge 32 generally comprises: a main body 40, an inletcap 42, the resin bed 34, and an outlet cap 44. In the embodimentillustrated, fluid is routed into the cartridge 32 through the inlet cap42 that is located at a bottom 46 of the cartridge 32. In the embodimentillustrated, a small open header chamber 48 prior to the resin bed 34 isused to distribute the flow of fluid evenly across the cross-section ofthe cartridge 32 and thereby the resin bed 34. The fluid preferablyflows upwardly through the resin bed 34.

[0079] In the embodiment illustrated, downstream of the final section ofthe resin bed 34 there is located another open header chamber 50. Thesecond open header chamber 50 is located before a gas separation chamber52. The second header chamber 50 is used to maintain an even fluidvelocity distribution throughout the resin bed 34.

[0080] The liquid level in the gas separation chamber 52 is maintainedwithin a specified range to provide an air space above the liquid in thecartridge 32. Gases that are produced during therapy, e.g., carbondioxide, are vented from the cartridge 32 to the environment through apassage 54 on the outlet cap 44. If desired, this passage 54 may includea filter member. A submerged, or partially submerged, barrier in the gasseparation chamber 52 produces a flow pattern that restricts gases frombeing drawn to the liquid outlet.

[0081] At the outlet cap 44 of the cartridge 32 the liquid outlet port58 is located. The liquid outlet 58 port removes liquid from the chamberof the cartridge 32 through the outlet cap 44 using a siphon action. Ifdesired, an additional port may be used to add a chemical concentrate tothe volume of liquid in the gas separation chamber to reconstitute thechemical composition of the fluid outflow.

[0082] In an embodiment, the interior of the cartridge 32 has a roughsurface. The rough surface is designed so that it prevents fluid fromflowing along the sides of the exterior by passing the resin bed 34.

[0083] The resin bed 34, in part, functions to remove waste. In thisregard, generally waste is removed using a two-step process. The stepsinclude an enzymatic conversion of urea using urease followed bysubsequent removal of the conversion byproducts. In the enzymaticreaction, one mole of urea is decomposed into two moles of ammonia andone mole of carbon dioxide. Ammonia (NH₃) is primarily (>95%) present asammonium ion (NH₄ ⁺), since its pKa of 9.3 is substantially greater thanthe solution pH. The carbon dioxide that is formed can either be presentas dissolved carbon dioxide or as bicarbonate ion, depending on thesolution pH. Since the pKa for this equilibrium is 6.1, both species maybe present in substantial quantities under conditions of use. Inaddition, if the solution is in communication with a gas phase, thedissolved carbon dioxide is in equilibrium with the carbon dioxidepresent in the gas phase.

[0084] The resin bed includes at least four layers, although more layerscan be used. Generally, the layers of the resin bed comprise at least: aurease layer; a layer of zirconium phosphate; a layer of zirconiumoxide; and a layer of carbon.

[0085] It should be understood that various changes and modifications tothe presently preferred embodiments described herein will be apparent tothose skilled in the art. Such changes and modifications can be madewithout departing from the spirit and scope of the present invention andwithout diminishing its intended advantages. It is therefore intendedthat such changes and modifications be covered by the appended claims.

The invention is claimed as follows:
 1. A method of producing a zirconium oxide composition, the method comprising the steps of: preparing a reaction solution including a base solution and a zirconyl salt solution including a zirconyl salt in isopropanol and water; mixing the reaction solution; heating the reaction solution at a reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 2. The method of claim 1 wherein the zirconyl salt comprises a zirconyl chloride octahydrate.
 3. The method of claim 1 wherein the base solution includes a base material selected from the group consisting of sodium hydroxide, ammonium hydroxide and combinations thereof.
 4. The method of claim 1 wherein a volume ratio of isopropanol to water in the zirconyl salt solution ranges from about 5:1 to about 2:1.
 5. The method of claim 1 wherein the reaction solution is mixed at room temperature.
 6. The method of claim 5 wherein the reaction solution is mixed for about 2 hours to about 20 hours.
 7. The method of claim 1 wherein the reaction solution is maintained at the reflux temperature for about 2 hours to about 20 hours.
 8. The method of claim 1 wherein the zirconium oxide precipitate is washed in a solvent selected from the group consisting of ethanol, water and combinations thereof.
 9. The method of claim 1 wherein the zirconium oxide precipitate has a particle size greater than about 10 microns.
 10. A method of producing a zirconium oxide composition, the method comprising the steps of: preparing a zirconyl salt solution including a zirconyl salt in isopropanol and water; heating the zirconyl salt solution at a reflux temperature; adding a base solution to the zirconyl salt solution at the reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 11. The method of claim 10 wherein the zirconyl salt comprises zirconyl chloride octahydrate.
 12. The method of claim 10 wherein a volume ratio of isopropanol to water ranges from about 5:1 to about 2:1.
 13. The method of claim 10 wherein the zirconyl salt solution is heated at the reflux temperature for about 1 hour to about 6 hours.
 14. The method of claim 10 wherein the zirconyl salt solution is maintained at the reflux temperature for about 1.5 hours to about 20 hours subsequent to addition of the base solution.
 15. The method of claim 14 wherein the base solution includes a base material selected from the group consisting of sodium hydroxide, ammonium hydroxide and combinations thereof.
 16. The method of claim 10 wherein the zirconium oxide precipitate is washed in a solvent selected from the group consisting of water, ethanol and combinations thereof.
 17. The method of claim 10 wherein the zirconium oxide precipitate has a particle size greater than about 10 microns.
 18. A method of increasing sorption capacity of a zirconium oxide composition in crystalline form, the method comprising the steps of: mixing at least a base solution and a zirconyl salt solution including a zirconyl salt in isopropanol and water thereby forming a reaction solution; heating the mixed solution at a reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 19. The method of claim 18 wherein the zirconyl salt comprises a zirconyl chloride octahydrate.
 20. The method of claim 18 wherein the base solution includes a base material selected from the group consisting of sodium hydroxide, ammonium hydroxide and combinations thereof.
 21. The method of claim 18 wherein a volume ratio of isopropanol to water in the zirconyl salt solution ranges from about 5:1 to about 2:1.
 22. The method of claim 18 wherein the reaction solution is mixed at room temperature.
 23. The method of claim 18 wherein the reaction solution is maintained at the reflux temperature for about 2 hours to about 20 hours.
 24. The method of claim 18 wherein the zirconium oxide precipitate is washed in a solvent selected from the group consisting of ethanol, water and combinations thereof.
 25. The method of claim 18 wherein the zirconium oxide composition has a sorption capacity for a phosphorous-containing constituent of greater than about 20 mg of phosphorous per gram of the zirconium oxide composition.
 26. A method for increasing sorption capacity of a zirconium oxide composition in a crystalline form, the method comprising the steps of: preparing a zirconyl salt solution including a zirconyl salt in isopropanol and water; heating the zirconyl salt solution at a reflux temperature; adding a base solution to the zirconyl salt solution at the reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 27. The method of claim 26 wherein the zirconyl salt comprises a zirconyl chloride octahydrate.
 28. The method of claim 26 wherein a volume ratio of isopropanol to water ranges from about 5:1 to about 2:1.
 29. The method of claim 26 wherein the zirconyl salt solution is heated at the reflux temperature for about 1 to about 6 hours.
 30. The method of claim 29 wherein the zirconyl salt solution is maintained at the reflux temperature for about 1.5 hours to about 20 hours subsequent to addition of the base solution.
 31. The method of claim 26 wherein the zirconium oxide precipitate is washed in a solvent selected from the group consisting of water, ethanol and combinations thereof.
 32. The method of claim 26 wherein the zirconium oxide composition has a sorption capacity for a phosphorous-containing constituent of greater than about 20 mg of phosphorous per gram of the zirconium oxide composition.
 33. A composition having an effective sorption capacity for a phosphorous-containing constituent, the composition comprising a zirconium oxide composition in crystalline form produced by the process of: preparing a reaction solution including a base solution and a zirconyl salt solution including a zirconyl salt in isopropanol and water; mixing the reaction solution; heating the reaction solution at a reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 34. The composition of claim 33 wherein the zirconium oxide composition is capable of removing the phosphorous-containing constituent in solution at greater than about 20 mg of phosphorous per gram of the zirconium oxide composition.
 35. The composition of claim 34 wherein the composition is used in ion exchange chromatography.
 36. The composition of claim 34 wherein the composition is used in a device capable of removing one or more constituents including the phosphorous-containing constituent from a physiological solution.
 37. The composition of claim 36 wherein the device is used during dialysis therapy.
 38. The method of claim 34 wherein a volume ratio of isopropanol to water in the zirconyl salt solution ranges from about 5:1 to about 2:1.
 39. The method of claim 33 wherein the zirconium oxide precipitate is sufficient in size to promote a sorption capacity that ranges from about 27 mg to at least about 29 mg of phosphorous per gram of the zirconium oxide composition.
 40. A composition having an effective sorption capacity for a phosphorous-containing constituent, the composition comprising a zirconium oxide composition in crystalline form produced by the process of: preparing a zirconyl salt solution including a zirconyl salt in isopropanol and water; heating the zirconyl salt solution at a reflux temperature; adding a base solution to the zirconyl salt solution at the reflux temperature; forming a zirconium oxide precipitate; and washing and drying the zirconium oxide precipitate.
 41. The composition of claim 40 wherein the zirconium oxide composition is capable of removing the phosphorous-containing constituent in solution at greater than about 20 mg of phosphorous per gram of the zirconium oxide composition.
 42. The composition of claim 41 wherein the composition is used in ion exchange chromotography.
 43. The composition of claim 41 wherein the composition is used in a device capable of removing one or more constituents including the phosphorous-containing constituent from a physiological solution.
 44. The composition of claim 43 wherein the device is used during dialysis therapy.
 45. The composition of claim 40 wherein a volume ratio of isopropanol to water ranges from about 5:1 to about 2:1.
 46. The method of claim 40 wherein the zirconium oxide precipitate is sufficient in size to promote a sorption capacity that ranges from about 27 mg to at least about 29 mg of phosphorous per gram of the zirconium oxide composition. 